This proposal uses the fruit fly, Drosophila melanogaster, as a model to study the pathways regulating responses to free base "crack about cocaine. This model organism shows conservation with vertebrate animal models both in the types of cocaine induced behaviors and in the biochemical and signaling pathways underlying these behaviors, it also shows sensitization to repeated cocaine exposures, a process that is likely to represent a component of the addictive process in humans. The current proposal focusses on the neural adaptations and signaling pathways leading to sensitization. The first two aims are directed at understanding two novel pathways required for sensitization in Drosophila that were identified in the previous funding period: In the first aim, the mechanisms by which the trace amine tyramine and the gene inactive are required for cocaine sensitization will be determined. In the second aim, the mechanisms by which the circadian gene products function in cocaine sensitization will be determined. The third aim will focus on the biogenic amine pathways and the direct targets of cocaine, the dopamine and serotonin transporters. For each of the above aims, potential genetic screens are proposed that could detect novel genes interacting with the given pathways. In the fourth aim, global changes in brain gene expression as a function of cocaine exposure and sensitization will be examined in order to identify new genes candidates involved in pathways modulating cocaine responses.